Preparation of cis-diamminediaquaplatinum(II) nitrate

ABSTRACT

A process is provided for preparing cis-[Pt(NH2)3(H2O)2](NO3)2 by a process comprising preparing cis-Pt(NH3)2I2 from K2PtI4 under controlled conditions of temperature and pH and converting the resultant cis-Pt(NH3)2I2 to the diaqua complex with AgNO3 under controlled conditions.

This is a division of application Ser. No. 241,946, filed Mar. 9, 1981, now U.S. Pat. No. 4,332,780 which in turn is a continuation-in-part of application Ser. No. 65,553, filed Aug. 16, 1979, now U.S. Pat. No. 4,273,755.

The present invention relates to the preparation of cis-platinum(II) complexes. More specifically it concerns improved methods of preparing cis-diamminedichloroplatinum(II) and intermediate compounds used in such preparation.

Cis-diamminedichloroplatinum(II) is not a new compound. It was first reported in 1844 and named Peyrone's chloride after its inventor. Recently, this compound has been of particular interest because it has been found to have anti-cancer activity. When used as an anti-cancer agent the compound must be exceedingly pure. Specifications set up by the National Cancer Institute (HCI) require that to be acceptable the salt should contain no more than 1% of the trans-isomer. There is also evidence that the presence of any ionic species, e.g. Magnus' green salt and silver, in the final product should be as low as possible. Because platinum is so expensive, the yields should be high, otherwise the process would not be commercially acceptable. Several syntheses are known but all give unacceptable quantities of both the trans-isomer and the double Magnus' green salt, [Pt(NH₃)₄ ](PtCl₄) as co-precipitates. A few companies are presently preparing cis-Pt(II) salts of acceptable purity but the methods used are proprietary.

R. J. Speer et al in "Cancer Chemotherapy Reports" Part I 59 (3), May/June 1975 indicate that cis-diamminedichloroplatinum(II) is rather toxic and that it has a low therapeutic index that is very dependent on its purity. They also recommend alternative routes to the synthesis and purification of the compound. One method for synthesis is that suggested in the literature by Kauffman and Cowan and the other by Dhara. The purification technique recommended is rather sparse in details, and details are lacking in conditions used in the various steps in the alternative methods for synthesis. The present method is an improvement over the alternative methods with respect to specific steps and with respect to the overall method for producing cis-Pt(NH₃)₂ Cl₂.

INVENTION

In accordance with the present invention a cis-diamminediiodoplatinum(II) complex, cis-Pt(NH₃)₂ I₂, of high purity and in high yield is prepared from potassium tetraodoplatinum(II) salt by a method comprising: adding an aqueous solution of ammonium hydroxide to an aqueous dispersion of potassium tetraiodoplatinum(II), said tetraiodo salt having the formula K₂ PtI₄, under a controlled gradually rising temperature profile, preferably stepwise between about 40° C. and about 60° C., while controlling the ammonium hydroxide addition so that the pH does not exceed approximately 7.5, and preferably the pH does not exceed approximately 7. The addition of NH₄ OH is controlled by slow addition, stirring the mixture vigorously during the addition, and monitoring the pH during the addition. Under these conditions, yields of at least about 91% cis-Pt(NH₃)₂ I₂ can be obtained, and typically yields of 91-97%. Using this technique as a step in a route in preparing cis-Pt(NH₃)₂ Cl₂ as the product, the crude product can be obtained with little or no Magnus' green salt and less than 1% of the trans-isomer.

As a further aspect of the invention cis-diamminediaquaplatinum(II) nitrate (i.e. cis-[Pt(NH₃)₂ (H₂ O)₂ ](NO₃)₂) is prepared from a cis-diamminediiodoplatinum(II) salt by a method comprising slowly adding the cis-diamminediiodoplatinum(II) to an aqueous solution of silver nitrate at room temperature and with rapid stirring and then warming the solution to no higher than about 50° C. The conversion for this method is essentially quantitative.

To produce the cis-diaqua salt with minimum silver ion in solution, the amount of AgNO₃ used is monitored carefully. For example, the AgNO₃ may be used slightly under stoichiometric amount. After separation of the silver iodide precipitate, a small amount (e.g., 0.5 gram relative to 200 g of product in 2500 ml solution) of solid KCl (or NaCl) is stirred into the filtrate to precipitate residual Ag⁺ and the resultant product is filtered to remove any precipitate. Alternatively, avoidance of unreacted Ag⁺ in solution can be effected by using a Ag/AgCl electrode.

In still another aspect of the present invention cis-diamminedichloroplatinum(II) is produced in high purity and in high yield from cis-diamminediaquaplatinum(II) nitrate by a method comprising rapidly adding solid MCl (M=, e.g. K, Na) to a solution of cis-diamminediaquaplatinum(II) nitrate at room temperature, warming the mixture to be a temperature of about 65° C. to 75° C., e.g., 70° C., and holding it at temperature to allow completion of the reaction permitting the resultant product to cool to a temperature no lower than about 10° C., e.g. to about 15° C. and preferably to room temperature, and then, without permitting the product to stand, separating the precipitate from the solution.

By using the combined preparation steps given above for preparing the cis-diamminedichloroplatinum(II) from the tetraiodoplatinum(II) salt high yields of the crude product can be obtained with substantially no Magnus' green salt and less than 1% trans-isomer.

The crude cis-diamminedichloroplatinum(II) can be purified by one or more recrystallizations from 0.1 N HCl by adding to the dilute hydrochloric acid solution, heating to 100° C., filtering hot and permitting the solution to cool to room temperature and/or by recrystallization at room temperature from N,N'dimethylformamide (DMF) with 0.1 N HCl addition.

In accordance with another aspect of the present invention the tetrachloro salt of platinum(II) is produced in improved yield from K₂ PtCl₆ with hydrazine dihydrochloride by mixing aqueous solutions of the reactants at substantially room temperature.

To insure high purity of the end product, the synthesis must be made with very high purity elemental platinum as the initial material and very high purity reagents. Highly pure chloroplatinic acid is commercially available. If desired, elemental platinum can be converted to chloroplatinic acid, e.g. with aqua regia, using methods known in the art.

Chloroplatinic acid can be converted to the insoluble K₂ PtCl₆ by treatment with potassium chloride. The conversion can be to the sodium salt with NaCl, but potassium is preferred for obtaining a higher yield. This reaction proceeds in an aqueous medium typically at a temperature in the range of about 55° to 60° C., preferably about 55° C. When cooled to 0° C., a very good yield of the platinum salt can be obtained. No alcohol is necessary.

DESCRIPTION OF PREFERRED EMBODIMENTS

It will be appreciated that tetrachloro and hexachloro salts of platinum(II) and (IV) such as K₂ PtCl₄ and K₂ PtCl₆ are commercially available and that each of the improved steps of the present invention can be carried out at any stage in the synthesis. The following description of the present process, however, will show a preferred embodiment of the present invention starting with high purity chloroplatinic acid and obtaining material which will meet National Cancer Institute (NCI) specification of Dec. 9, 1975 for compound No. NSC-119,875 (cis-Pt[NH₃ ]₂ Cl₂). In the following description and the examples which follow: All reactions are carried out using a magnetic stirrer. All materials used are very pure. Room temperature means about 25° C. Yields were determined by wet chemical analysis initially and thereafter gravimetrically, except if otherwise indicated.

Step 1 Reaction: H₂ PtCl₆ +2KCl→K₂ PtCl₆ +2HCl

An aqueous solution containing roughly 0.25 moles per liter of chloroplatinic acid heated to about 55° C.×5° C. is treated by slow, dropwise addition of a concentrated aqueous solution of KCl. The amount of KCl used is stoichiometric for complete conversion to K₂ PtCl₆ which forms as a yellow precipitate. The reaction mixture need not be heated. However, it is preferred to elevate the temperature moderately, e.g. to about 50° C., to ensure that the reaction goes to completion and that no KCl gets entrapped in the K₂ PtCl₆. Also, to ensure complete conversion a very slight excess of KCl can be added. The product is cooled to 0° C. and permitted to stand, e.g. overnight, to ensure complete precipitation.

After filtration, the residue is washed with cold distilled water, e.g., with three 500 ml portions of water, and then with absolute ethyl alcohol, e.g., with a 500 ml portion of alcohol. The washed residue is dried, e.g., for 2 hours at 110° C. The filtrate is kept for platinum recovery. A yield of 95% has been obtained.

Step 2 Reaction: 2K₂ PtCl₆ +N₂ H₄.2HCl→2K₂ PtCl₄ +N₂ +6HCl

The dried K₂ PtCl₆ (about 0.5 mole) is dispersed in 2000 ml of distilled water and an aqueous solution of N₂ H₄.2HCl containing a 5% excess of stoichiometric amount, is added dropwise with vigorous stirring. The addition is done at room temperature and the flow of reagent is adjusted so that addition takes 30 minutes. Thereafter the resultant mixture is warmed to 50°-60° C. until the yellow precipitate disappears. This takes typically one hour. Thereafter the resultant red solution is heated to 85° C. and held there for 15 minutes, then cooled to room temperature and refrigerated overnight. Essentially complete conversion to the tetrachloride can be achieved without decomposition to elemental Pt.

To ensure the removal of any unreacted K₂ PtCl₆, the product of Step 2 is cooled to about 0° C. and permitted to stand. For convenience the product may be refrigerated overnight. In carrying out Step 2 care should be taken to add sufficient hydrazine to react with the K₂ PtCl₆, only slight excess, e.g. 5% is used, since with too great an excess of hydrazine causes reduction to Pt°. The vessel used for the reaction should be free from cracks or scratches which may serve as sites for nucleation of Pt°.

Step 3 Reaction: K₂ PtCl₄ +4KI→K₂ PtI₄ +4HCl

The potassium tetrachloroplatinum(II) solution is warmed to 40° C. and an aqueous solution of 10 molar KI is added dropwise in sufficient amount for complete conversion to the tetraiodo salt. A black precipitate of K₂ PtI₄ begins to form. Typically this takes about 1 hour, after which the solution is heated to 85° C. and held there for 15 minutes. Essentially complete conversion can be achieved. The product is cooled to at least 40° C. for use in the next step. Alternatively the temperature may be maintained at 40° C. or heated up to less than 85° C., e.g. 50° or 60° C.

Step 4 Reaction: K₂ PtI₄ +2NH₄ OH→cis-Pt(NH₃)₂ I₂ +2KI+2H₂ O

To the K₂ PtI₄ containing solution of Step 3 at 40° C., a diluted solution of NH₄ OH is added dropwise using a pH meter so that pH of about 7.5 is not exceeded during the addition. K₂ PtI₄ has a pH of about 4.9 in water at room temperature. However, sufficient NH₄ OH must be added to neutralize the HCl in solution as well as to react with the K₂ PtI₄. (If the K₂ PtI₄ is used as a water dispersion the reaction would only require sufficient NH₄ OH to react with the K₂ PtI₄, using proper precautions with regard to pH, temperature and the manner in which the NH₄ OH is added.) The dilute NH₄ OH is added until the black precipitate disappears, typically 3 to 4 hours. The solution is warmed to 60° C. for 1 hour, adding dilute NH₄ OH as needed to pH up to about 7.5, and then the reaction mixture is cooled to room temperature. A dark greenish brown precipitate forms which is filtered. The resultant precipitate is washed with distilled water and then absolute ethyl alcohol, e.g., three washes with 500 ml water and one with 500 ml alcohol. The filtrate is kept for platinum recovery. The yield is typically about 91% for Steps 2, 3 and 4, but a yield as high as 97% has been obtained.

Alternatively the solution may be maintained between about 40° C. to 60° C. after the addition of NH₄ OH. After the reaction mixture is cooled to room temperature a light brown precipitate which forms is filtered. The yield is typically less than when the higher temperature is used, i.e., about 80-85%, but the product formed is purer and the purity is easier to control when the preparation involves large quantities, i.e., of the order of about 1 kilogram or higher.

Step 5 Reaction: cis-Pt(NH₃)₂ I₂ +2AgNO₃ +2H₂ O→cis-[Pt(NH₃)₂ (H₂ O)₂ ](NO₃)₂ +2AgI

After dissolving AgNO₃ in distilled water, solid cis-Pt(NH₃)₂ I₂ is added slowly to the solution at room temperature with rapid stirring. Typically addition of the cis-diamminediiodoplatinum(II) to the solution of AgNO₃ takes about 30 minutes, and the resultant mixture is stirred for an additional period of time, e.g., about 10 minutes, and then it is warmed to 50° C. and held there for a short period of time, e.g., 15 minutes, to ensure complete reaction. Thereafter the reaction mixture is cooled to room temperature and filtered to remove the AgI precipitate.

The AgI precipitate is washed, e.g., with three 500 ml portions of distilled water.

When it is particularly desirable to minimize the silver level in the product, the AgNO₃ reagent is used slightly below the stoichiometric amount. To the separated filtrate after reaction with AgNO₃, a small amount of solid KCl, e.g. 0.5 g KCl, is added and after stirring at room temperature for a short period, the product is filtered. Filtration can be carried out through the AgI precipitate and the residue can be kept for recovery of Ag.

The yield of the cis-diaqua salt in solution is quantitative. The high yields are insured by adding the cis-diamminediiodoplatinum(II) to the AgNO₃ solution. At room temperature the KCl serves to precipitate Ag⁺ in solution. When the AgNO₃ is added, for example, to a hot solution of the iodo salt, as recommended in the art, the yields are not as high. In addition if reaction temperature is permitted to go above 50° C., e.g. to 65° C., then yields are not as high.

Step 6 Reaction: cis-[Pt(NH₃)₂ (H₂ O)₂ ](NO₃)₂ +2KCl→cis-Pt(NH₃)₂ Cl₂ +2KNO₃ +2H₂ O

To the filtrate of Step 5 at room temperature and with stirring is added solid KCl in an amount of 10% excess, as quickly as possible. The mixture is warmed to 70° C. and held there for completion of the reaction, typically 1 hour, and the product allowed to cool to room temperature while stirring to avoid temperature gradient. As soon as the product is at room temperature, it is filtered and the residue washed. Washing is carried out with three 500 ml portions of distilled water followed by one 500 ml portion of absolute ethyl alcohol.

Co-precipitation of impurities can be avoided by cooling only to room temperature. Further cooling below room temperature, e.g., to 0° C. resulted in the appearance of traces of Magnus' green salt and other impurities in the final product.

A yield of 95% crude cis-Pt(NH₃)₂ Cl₂ for Steps 6 and 7 has been obtained. The total yield from Steps 1 through 7 is typically 79%. All platinum can be recovered from discarded materials.

Step 7 Reaction: Purification of Crude cis-Pt(NH₃)₂ Cl₂ (a) First Recrystallization

The crude product is added to 0.1 N HCl (about 1 g product to 35 ml 0.1 N HCl), and the solution is warmed to 100° C., filtered hot and then the filtrate is cooled to room temperature for recrystallization.

(b) Second Recrystallization

Repeat of first recrystallization step.

(c) Third Recrystallization

Before the third recrystallization step, a test for solubility according to the aforementioned NCI specification should be carried out. If the material does not pass the solubility test an alternative third recrystallization step is carried out as follows: The product of the second recrystallization step is dissolved in DMF. About 50 ml DMF/g of the cis-Pt product is sufficient. After filtration an equivalent volume of 0.1 N HCl is added with stirring and the mixture is permitted to stand with stirring for 20 minutes. The purified cis-Pt product precipitates and after filtration the residue is washed with absolute alcohol and vacuum dried.

It was found that the present product could be retained for a period of 3 days in 0.1 N HCl without any transformation to trans observed by paper chromatography test.

The above method is an improvement over known methods for producing cis-Pt(NH₃)₂ Cl₂ in that it: gave (1) unexpectedly high yield of the desired product, (2) a pure cis-isomer free of Magnus' green salt and of the trans-isomer, and (3) a final compound with very low silver content. For better understanding of the present invention by persons skilled in the art, some specific examples are given below by way of illustration.

EXAMPLE 1

Experiments were run essentially as described in Step 2 above, in which K₂ PtCl₆ is reduced to K₂ PtCl₄ using hydrazine, with the following variations:

    ______________________________________                                         Exp.             Initial                                                       Type   Reagent   Temperature                                                                               Pt Deposit (Pt°) Observed                   ______________________________________                                         A-1    N.sub.2 H.sub.4.2HCl                                                                     Room Temp. None                                               B-1    N.sub.2 H.sub.4                                                                          Room Temp. Pt° immediately                             C-1    N.sub.2 H.sub.4.2HCl                                                                     50°-65° C.                                                                  Some Pt° on sides of                        ______________________________________                                                                     beaker                                        

EXAMPLE 2

Experiments were run essentially as described in Step 4 above, in which K₂ PtI₄ is converted to cis-Pt(NH₃)₂ I₂ using NH₄ OH, with the following variations:

    ______________________________________                                         Exp.                             Yield                                         Type Reagent  Condition          cis-Pt(NH.sub.3).sub.2 I.sub.2                ______________________________________                                         A-2  NH.sub.4 OH                                                                             Temp. control gradual to                                                                          96%                                                         60° C. & gradual addition of                                            NH.sub.4 OH & control pH not to                                                exceed 7                                                         A-2a NH.sub.4 OH                                                                             Temp. control gradual to                                                                          85%                                                         and maintain at 40° C. &                                                gradual addition of                                                            NH.sub.4 OH & control pH not to                                                exceed 7.5                                                       B-2  NH.sub.4 OH                                                                             Stoichiometric NH.sub.4 OH added                                                                  77%                                                         to solution at 60° C. & with-                                           out pH control                                                   B-2a NH.sub.4 OH                                                                             Stoichiometric NH.sub.4 OH added                                                                  77%                                                         to solution at 40° C. & with-                                           out pH control                                                   ______________________________________                                    

The problem with adding NH₄ OH stoichiometrically at either 40° C. or 60° C. without pH control is that the ammonium ion concentration increases to a high level which results in unwanted amounts of Magnus' green salt when the cis-Pt(NH₃)₂ I₂ is ultimately converted to the cis-Pt(NH₃)₂ Cl₂.

EXAMPLE 3

Experiments were carried out essentially as described in Step 5 above, in which cis-Pt(NH₃)₂ I₂ in aqueous solution is converted with AgNO₃ to the cis-[Pt(NH₃)₂ (H₂ O)₃ ](NO₃)₂, with the following variations and results:

    ______________________________________                                         Exp.                     Yield*                                                Type  Variation Addition Temperature Crude                                     ______________________________________                                         A-3   cis-iodo salt added to AgNO.sub.3                                                                 Room Temp.  95%                                       B-3   cis-iodo salt added to AgNO.sub.3                                                                 50° C.                                                                              90%                                       C-3   cis-iodo salt added to AgNO.sub.3                                                                 90° C.                                                                              78%                                       D-3   AgNO.sub.3 added to cis-iodo salt                                                                 Room Temp.  84%                                       ______________________________________                                          *Since it is difficult to analyze for the diaqua compound, analysis was        made for the yield of crude cisPt(NH.sub.3).sub.2 Cl.sub.2 (i.e., the          product obtained after carrying out step 6 on the filtrates obtained from      the tests of this experiment).                                           

EXAMPLE 4

Experiments were carried out essentially as described in Step 6 above, in which cis-[Pt(NH₃)₂ (H₂ O)₂ ](NO₃)₂ in solution is treated with KCl to form the crude cis-Pt(NH₃)₂ Cl₂, with the following variations and results:

    ______________________________________                                                                           Observation                                  Exp. Type                                                                               Conditions       Yield   Magnus' Salt                                 ______________________________________                                         A-4      1 - Reaction at Room Temp.                                                                      95%     None                                                  2 - Warm to 70° C.                                                      3 - Cool to 25° C. & Filter                                             Immediately                                                           B-4      1 - Reaction at Room Temp.                                                                      80%     None                                                  2 - Cool at 25° C. & Filter                                             Immediately                                                           C-4      1 - Reaction at Room Temp.                                                                      --      Layer of                                              2 - Cool to 0° C. Green Salt                                   ______________________________________                                    

In another set of experiments three identical solutions containing cis-[Pt(NH₃)₂ (H₂ O)₂ ](NO₃)₂ were treated with KCl and the crude cis-platinum complex was permitted to form under the conditions of A-4 and after separation of the precipitate at 25° C., the filtrates were treated, respectively, under the three different conditions noted below, with the following observations:

    ______________________________________                                         Exp.   Conditions         Observation                                          ______________________________________                                         D-4    Filtrate No. 1 on cold plate                                                                      More ppt of cis-Pt                                          Allowed to cool to 15° C.                                                                  formed - no green                                           Allowed to cool to between                                                                        salt                                                        9-10° C.    Magnus' green salt                                                             came down                                            E-4    Filtrate No. 2 stood at RT                                                                        Traces of Magnus'                                                              green salt in 3 hrs.                                 F-4    Filtrate No. 3 stood at RT                                                                        Traces of Magnus'                                                              green salt in 31/2                                                             hrs.                                                 ______________________________________                                    

The tests showed that Magnus' green salt formed when the temperature fell below about 10° C. and when the reaction medium was permitted to stand at room temperature. Even though the Magnus' green salt did not form immediately, the tests show that it is advisable not to let the reaction medium stand at room temperature.

To maximize yield and ensure purity, the cis-Pt(NH₃)₂ Cl₂ can be separated from solution in a stepwise fashion. For example, after cooling to room temperature the product is immediately filtered and the solution is permitted to stand until a further precipitate is formed. This is repeated until the formation of a green salt is observed.

EXAMPLE 5

Experiments were carried out essentially as described in Steps 3 and 4 above in which K₂ PtCl₄ is converted to K₂ PtI₄ using KI, and then K₂ PtI₄ is converted to cis-Pt(NH₃)₂ I₂ using a dilute solution of NH₄ OH under pH control, with the following variations in pH control in Step 4 and results:

    ______________________________________                                         Exp.   pH     % Yield(1) Appearance of Product of Step 4                       ______________________________________                                         A-5    7      91(2)      Dark greenish brown                                   B-5    7.5    88         Dark brown                                            C-5    8      67         Light brown                                           ______________________________________                                          (1)Yield based on Steps 3 and 4.                                               (2)Average yield based on 7 tests.                                       

EXAMPLE 6

Samples were prepared using the method of the present invention essentially as described above in Steps 1 through 6 and then purified by recrystallization twice according to the 0.1 N HCl method of Step 7. Samples of the final product were screened according to the aforementioned NCI specification for the chemical NSC-119,875.

(A) In the paper chromatography test, no trans-isomer was detected within the limit of detection (about 178%) (14 samples tested).

(B) Wet chemical analysis on a typical sample of twice recrystallized product was submitted for analysis of platinum, chlorine and ammonia. The results compared with the HCI specification as follows:

    ______________________________________                                                       Spec.         Analysis                                           Elemental Component                                                                          (%)           (%)                                                ______________________________________                                         Platinum      65.02  0.30         65.2                                         Chlorine      23.63  0.30         23.5                                         Hydrogen      2.02   0.30                                                                                        11.1 (as NH.sub.3)                           Nitrogen      9.3    0.30                                                      ______________________________________                                    

(C) The cis-Pt(NH₃)₂ Cl₂ was observed to be an orange yellow solid which decomposed at 270° C.

(D) When a sample was refluxed with thiourea in 0.1 N HCl yellow crystals formed which decomposed at 242° C.

(E) IR spectrum run on a Beckman IR-20-X Infrared Spectrometer was compatible with the model spectrum furnished by NCI.

EXAMPLE 7

Experiments were run essentially as described in Step 1 above, in which H₂ PtCl₆ is converted to K₂ PtCl₆, with the following variations:

    ______________________________________                                         Exp.       Reaction Temperature                                                                          Yield                                                ______________________________________                                         A-7        50° C.  95-98%                                               B-7        RT             92-93%                                               ______________________________________                                    

EXAMPLE 8

A sample of cis-Pt(NH₃)₂ Cl₂ was prepared using the method of the present invention essentially as described above in Steps 1 through 6 and then purified three times by the recrystallization from 0.1 N HCl. The sample was sent to an independent laboratory for analyses and it was reported that a HPLC (High Performance Liquid Chromatography) recording showed only peaks for cis-Pt(NH₃)₂ Cl₂ and no other peaks. High sensitivity tracings at the region where small peaks for Magnus' green salt and trans-isomer might appear showed no evidence of such impurities in the product.

EXAMPLE 9

Samples of crude cis-Pt(NH₃)₂ Cl₂, prepared using the method of the present invention essentially as described above in Steps 1 through 6 and were analyzed for composition:

(1) An IR spectrum run on a Beckman IR-20-X Infrared Spectrometer showed ammine and chloride peaks compatible with the NCI model. An additional unidentified peak was observed at a wavelength of roughly 5.7.

(2) In a sample subjected to the NCI paper chromatography test, no trans-isomer was detected within the limit of detection (about 1/2%).

(3) Several samples were analyzed for silver content, and analysis showed less than 5 ppm silver.

Although the present invention has been described in conjunction with preferred embodiments, it is to be understood that modifications and variations may be resorted to without departing from the spirit and scope of the invention, as those skilled in the art will readily understand. Such modifications and variations are considered to be within the purview and scope of the invention and appended claims. 

What is claimed is:
 1. A process for preparing a cis-diamminediiodoplatinum(II) complex of high purity and in high yield from potassium tetraiodoplatinum(II) by a method comprising adding an aqueous solution of ammonium hydroxide to an aqueous dispersion of potassium tetraiodoplatinum(II), said tetraiodo compound having the formula K₂ PtI₄, under a controlled gradually rising temperature profile while controlling the ammonium hydroxide addition so that the pH does not exceed about 7.5, washing and drying the resultant precipitated cis-Pt(NH₃)₂ I₂, slowly adding the washed and dried cis-Pt(NH₃)₂ I₂ to an aqueous solution of AgNO₃ at room temperature and with rapid stirring, warming the silver-containing mixture to a maximum temperature of about 50° C. and maintaining the temperature of about 50° C. for a period of time sufficient substantially to complete the reaction, then cooling the resultant silver-containing reaction mixture to room temperature to form a solution containing cis-[Pt(NH₃)₂ (H₂ O)₂ ](NO₃)₂ and a AgI precipitate and separating the precipitated AgI from the solution containing cis-[Pt(NH₃)₂ (H₂ O)₂ ](NO₃)₂.
 2. A process according to claim 1, wherein the AgNO₃ reagent is used in an amount slightly below stoichiometric for complete conversion of cis-Pt(NH₃)₂ I₂, and after separation of the AgI, to the remaining solution is added MCl (where M=K or Na) in a small but effective amount for precipitating Ag⁺, and precipitated AgCl is separated from the solution, thereby forming a purified solution of cis-[Pt(NH₃)₂ (H₂ O)₂ ](NO₃)₂ with minimized Ag⁺ content.
 3. A process according to claim 1, wherein the Ag⁺ in solution containing cis-[Pt(NH₃)₂ (H₂ O)₂ ](NO₃)₂ is monitored with a silver/silver chloride electrode to minimize the Ag⁺ in solution.
 4. A process for preparing cis-[Pt(NH₃)₂ (H₂ O)₂ ](NO₃)₂ of high purity and in high yield comprising: slowly adding a concentrated aqueous solution of KCl to a solution of chloroplatinic acid at a temperature of about 50° to about 60° C., to precipitate K₂ PtCl₆, cooling the solution to about 0° C. and permitting it to stand to ensure complete precipitation, separating and washing the K₂ PtCl₆ precipitate, adding dropwise and at room temperature to an aqueous dispersion of the washed K₂ PtCl₆ an aqueous solution of N₂ H₄.2HCl in excess of the stoichiometric amount, warming the resultant mixture to about 60° C. until the dispersed K₂ PtCl₆ has dissolved, thereafter heating the solution stepwise up to about 85° C. thereby forming K₂ PtCl₄ in solution, adding an aqueous solution of KI to the aqueous solution of K₂ PtCl₄ to convert said K₂ PtCl₄ to the corresponding K₂ PtCl₄ at a temperature of about 40° C. and maintaining the solution at a temperature to about 40° C. to about 85° C. to maximize conversion to K₂ PtI₄ to a water dispersion of said K₂ PtI₄, at a temperature of about 40° C. adding a dilute solution of NH₄ OH slowly with stirring and with pH control so that the pH of 7.5 is not exceeded during the addition until the K₂ PtI₄ dispersion dissolves, maintaining the resultant solution at a temperature of about 40° C. to about 60° C. and adding additional NH₄ OH to a pH of about 7.5, then cooling the pH-adjusted solution to room temperature to precipitate cis-Pt(NH₃)₂ I₂, separating and washing the precipitated cis-Pt(NH₃)₂ I₂, adding the washed cis-Pt(NH₃)₂ I₂ to an aqueous solution of AgNO₃ while stirring and at room temperature, said AgNO₃ being present in a controlled amount to react with the cis-Pt(NH₃)₂ I₂ with minimum unreacted Ag, warming the silver-containing mixture to about 50° C. to ensure complete reaction and then cooling the resultant silver-containing mixture thereby forming a AgI precipitate and an aqueous solution containing cis-[Pt(NH₃)₂ (H₂ O)₂ ](NO₃)₂. 